HBV DNA polymerase regulates tumor cell glycogen to enhance the malignancy of HCC cells.

Abstract

The essential function of HBV DNA polymerase (HBV-DNA-Pol) is to initiate viral replication by reverse transcription; however, the role of HBV-DNA-Pol in HBV-associated HCC has not been clarified. Glycogen phosphorylase L (PYGL) is a critical regulator of glycogenolysis and is involved in tumorigenesis, including HCC. However, it is unknown whether HBV-DNA-Pol regulates PYGL to contribute to HCC tumorigenesis. Bioinformatic analysis, real-time quantitative PCR, western blotting, and oncology functional assays were performed to determine the contribution of HBV-DNA-Pol and PYGL to HCC development and glycolysis. The mechanisms of co-immunoprecipitation and ubiquitination were employed to ascertain how HBV-DNA-Pol upregulated PYGL. Overexpression of HBV-DNA-Pol enhanced HCC progression in vitro and in vivo. Mechanistically, HBV-DNA-Pol interacted with PYGL and increased PYGL protein levels by inhibiting PYGL ubiquitination, which was mediated by the E3 ligase TRIM21. HBV-DNA-Pol competitively impaired the binding of PYGL to TRIM21 due to its stronger binding affinity to TRIM21, suppressing the ubiquitination of PYGL. Moreover, HBV-DNA-Pol promoted glycogen decomposition by upregulating PYGL, which led to an increased flow of glucose into glycolysis, thereby promoting HCC development. Our study reveals a novel mechanism by which HBV-DNA-Pol promotes HCC by controlling glycogen metabolism in HCC, establishing a direct link between HBV-DNA-Pol and the Warburg effect, thereby providing novel targets for HCC treatment and drug development.